Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome.

Autor:	Jolly A; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Du H; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Borel C; University of Geneva Medical School, 1211 Geneva, Switzerland., Chen N; Department of Obstetrics and Gynaecology, Beijing 100730, China., Zhao S; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases and Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Chinese Academy of Medical Sciences, Beijing 100730, China., Grochowski CM; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Duan R; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Fatih JM; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Dawood M; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Salvi S; Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA., Muzny DM; Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA., Koch A; University of Tübingen, Department of Obstetrics and Gynecology, Tübingen, Germany., Rouskas K; Institute for Bioinnovation, Biomedical Sciences Research Center Al. Fleming, Vari, Athens 16672, Greece.; Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece., Glentis S; Institute for Bioinnovation, Biomedical Sciences Research Center Al. Fleming, Vari, Athens 16672, Greece., Deligeoroglou E; Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens 11527, Greece., Bacopoulou F; Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens 11527, Greece., Wise CA; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX, USA.; McDermott Center for Human Growth and Development, Department of Pediatrics and Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA., Dietrich JE; Department of Obstetrics and Gynecology, Houston, TX, USA.; Department of Pediatrics, BCM, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Van den Veyver IB; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.; Department of Obstetrics and Gynecology, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Dimas AS; Institute for Bioinnovation, Biomedical Sciences Research Center Al. Fleming, Vari, Athens 16672, Greece., Brucker S; University of Tübingen, Department of Obstetrics and Gynecology, Tübingen, Germany., Sutton VR; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA., Antonarakis SE; University of Geneva Medical School, 1211 Geneva, Switzerland.; Institute of Genetics and Genomics in Geneva, University of Geneva, 1205 Geneva, Switzerland.; Medigenome, the Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland., Wu N; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases and Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Chinese Academy of Medical Sciences, Beijing 100730, China., Coban-Akdemir ZH; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Zhu L; Department of Obstetrics and Gynaecology, Beijing 100730, China., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA.; Department of Pediatrics, BCM, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2023 Mar 29; Vol. 4 (3), pp. 100188. Date of Electronic Publication: 2023 Mar 29 (Print Publication: 2023).
DOI:	10.1016/j.xhgg.2023.100188
Abstrakt:	Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was used to further reproduce GREB1L findings in diverse genetic backgrounds. Proband and OMIM phenotypes annotated using the Human Phenotype Ontology were analyzed to quantitatively delineate the phenotypic spectrum associated with GREB1L variant alleles found in our MRKH cohort and those previously published. This study reports 18 novel GREB1L variant alleles, 16 within a multiethnic MRKH cohort and two within a congenital scoliosis cohort. Cohort-wide analyses for a burden of rare variants within a single gene identified likely damaging variants in GREB1L (MIM: 617782), a known disease gene for renal hypoplasia and uterine abnormalities (MIM: 617805), in 16 of 590 MRKH probands. GREB1L variant alleles, including a CNV null allele, were found in 8 MRKH type 1 probands and 8 MRKH type II probands. This study used quantitative phenotypic analyses in a worldwide multiethnic cohort to identify and strengthen the association of GREB1L to isolated uterine agenesis (MRKH type I) and syndromic MRKH type II. Competing Interests: J.R.L. has stock ownership in 23andMe and is a co-inventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, genomic disorders, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing (both ES and WGS) offered in the Baylor Genetics Laboratory (http://bmgl.com). J.R.L. and I.B.V. serve on the Scientific Advisory Board of BG. S.E.A. is the co-founder and CEO of Medigenome, The Swiss Institute of Genomic Medicine. (© 2023 The Author(s).)
Databáze:	MEDLINE
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